Skin cancer is the most common of all cancers and melanoma is the most serious and aggressive type of skin cancer. Melanoma accounts for less than 5% of skin cancer cases, yet it is responsible for a large majority of the deaths associated with skin cancer. Almost 70,000 people in the United States will be diagnosed with melanoma during 2010 and approximately 9,000 people are expected to die from the disease (American Cancer Society; www.cancer.org). Across the world the incidence of melanoma has been increasing at an alarming rate, with a lifetime risk of developing melanoma as high as 1/58 for males in the U.S. to 1/25 for males in Australia (Jemal et al., 2008, CA: Cancer J. Clin. 58:71-96). The survival rate is fairly high for individuals who are diagnosed with early stage melanoma and receive appropriate treatment. However, metastatic melanoma remains one of the most difficult cancers to treat and individuals with this advanced form have an average survival time of only nine to eleven months.
Signaling pathways normally connect extracellular signals to the nucleus leading to expression of genes that directly or indirectly control cell growth, differentiation, survival and death. In melanoma as well as a wide variety of cancers, signaling pathways are dysregulated and may be linked to tumor initiation and/or progression. Signaling pathways implicated in human oncogenesis include, but are not limited to, the Notch pathway, the Ras-Raf-MEK-ERK or MAPK pathway, the PI3K-AKT pathway, the CDKN2A/CDK4 pathway, the Bcl-2/TP53 pathway, and the Wnt pathway.
The Notch signaling pathway is a universally conserved signal transduction system. It is involved in cell fate determination during development including embryonic pattern formation and post-embryonic tissue maintenance. In addition, Notch signaling has been identified as a critical factor in the maintenance of hematopoietic stem cells (HSCs).
The Notch pathway has been linked to the pathogenesis of both hematologic and solid tumors and cancers. Numerous cellular functions and microenvironmental cues associated with tumorigenesis have been shown to be modulated by Notch pathway signaling, including cell proliferation, apoptosis, adhesion, and angiogenesis. (Leong et al., 2006, Blood, 107:2223-2233). In addition, Notch receptors and/or Notch ligands have been shown to play potential oncogenic roles in a number of human cancers, including acute myelogenous leukemia, B cell chronic lymphocytic leukemia, Hodgkin lymphoma, multiple myeloma, T cell acute lymphoblastic leukemia, brain cancer, breast cancer, cervical cancer, colon cancer, lung cancer, pancreatic cancer, prostate cancer, skin cancer and melanoma. (Leong et al., 2006, Blood, 107:2223-2233; Nickoloff et al., 2003, Oncogene, 22:6598-6608). Thus, the Notch pathway has been identified as a potential target for cancer therapy.
Previous studies demonstrated that antibodies to the human Notch ligand Delta-like ligand 4 (DLL4) can decrease the percentage of cancer stem cells or tumor initiating cells in some xenograft tumors. In addition, antibodies to mouse DLL4 were shown to result in hyperproliferation of tumor vasculature. (Hoeg et al., 2009, Cell Stem Cell, 5:168-177). These findings suggest that targeting the Notch pathway, for example with DLL4 antagonists, could help eliminate not only the majority of non-tumorigenic cancer cells, but the tumorigenic cancer stem cells responsible for the formation and recurrence of solid tumors.
The MAPK (mitogen-activated protein kinase) pathway has been shown to play key roles in various normal physiological processes such as cellular metabolism, cell cycle progression, cell death and neurological function. Mutations in the MAPK pathway have been shown to be very important in melanoma development in that up to 90% of melanomas and benign melanocytic neoplasms carry activating mutations in either B-raf or N-ras. In addition, it has been reported that 30-70% of malignant melanomas contain B-raf mutations and that a valine to glutamate change at position 600 accounts for approximately 80% of the mutations. (Davies et al., 2002, Nature, 417:949-954). These findings suggested that the MAPK pathway could be a potential target for new therapies for treatment of melanoma.
Numerous efforts to develop therapeutic agents that specifically target the mutated B-raf kinase are currently underway. However, these agents will have little or no effect in patients with a wild-type B-raf. In fact, patients without the V600E B-raf mutation have been excluded from on-going clinical trials. Thus, there is a need for new agents that could provide therapeutic benefit for this segment of melanoma patients.
As of 2010, there are only two FDA-approved drugs for metastatic melanoma, dacarbazine and interferon-alpha. However, only 10-20% of patients with advanced melanoma respond to either of these drugs. Furthermore, no new drug for treatment of melanoma has been approved in over fifteen years. Clearly, there is a need for new and/or more effective therapeutic agents for the treatment of melanoma and particularly metastatic melanoma.